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Original research
Experience of a 2-year spinal muscular atrophy NBS pilot study in Italy: towards specific guidelines and standard operating procedures for the molecular diagnosis
  1. Emanuela Abiusi1,
  2. Alessandro Vaisfeld1,
  3. Stefania Fiori1,
  4. Agnese Novelli1,
  5. Serena Spartano1,
  6. Maria Vittoria Faggiano1,
  7. Teresa Giovanniello2,
  8. Antonio Angeloni2,
  9. Giovanni Vento3,4,
  10. Roberta Santoloci5,
  11. Francesca Gigli4,
  12. Adele D'Amico6,
  13. Simonetta Costa3,
  14. Alessia Porzi3,
  15. Mara Panella5,
  16. Chiara Ticci7,
  17. Marta Daniotti7,
  18. Michele Sacchini7,
  19. Ilaria Boschi8,
  20. Enrico Bertini6,
  21. Antonio Lanzone5,9,
  22. Giancarlo Lamarca10,
  23. Maurizio Genuardi1,11,
  24. Marika Pane12,13,
  25. Maria Alice Donati7,
  26. Eugenio Mercuri12,13,
  27. Francesco Danilo Tiziano1,11
  28. on behalf of the Italian SMA-NBS group
    1. 1Section of Genomic Medicine, Department of Life Sciences and Public Health, Catholic University of Sacred Heart, Roma, Italy
    2. 2Department of Experimental Medicine, Newborn Screening Center-Clinical Pathology Unit, Sapienza University of Rome, University Hospital Policlinico Umberto I, Roma, Italy
    3. 3Section of Pediatrics, Department of Life Sciences and Public Health, Catholic University of Sacred Heart, Roma, Italy
    4. 4Neonatology Unit, Fondazione Policlinico Universitario IRCCS “A. Gemelli", Roma, Italy
    5. 5Obstetrics and Gynecology operating Unit, Fondazione Policlinico Universitario IRCCS “A. Gemelli, Roma, Italy
    6. 6Department of Molecular Medicine, Bambino Gesù Pediatric Hospital, Roma, Italy
    7. 7Unit of hereditary metabolic and muscular disorders, Meyer Children’s University Hospital, Firenze, Italy
    8. 8Forensic Medicine operating Unit, Fondazione Policlinico Universitario IRCCS “A. Gemelli”, Roma, Italy
    9. 9Section of Obstetrics and Gynecology, Department of Life Sciences and Public Health, Catholic University of Sacred Heart, Roma, Italy
    10. 10Newborn Screening, Clinical Chemistry and Pharmacology Laboratory, Meyer Children's University Hospital, Firenze, Italy
    11. 11Medical Genetics operating Unit, Fondazione Policlinico Universitario IRCCS “A. Gemelli”, Roma, Italy
    12. 12Section of Child Psychiatry, Department of Life Sciences and Public Health, Catholic University of Sacred Heart, Roma, Italy
    13. 13Child Psychiatry operating Unit, Fondazione Policlinico Universitario IRCCS “A. Gemelli”, Roma, Italy
    1. Correspondence to Professor Francesco Danilo Tiziano, Section of Genomic Medicine, Department of Life Sciences and Public Health, Universita Cattolica del Sacro Cuore Facolta di Medicina e Chirurgia, Roma 1 – 00168, Italy; francescodanilo.tiziano{at}unicatt.it

    Abstract

    Background Spinal muscular atrophy (SMA) is due to the homozygous absence of SMN1 in around 97% of patients, independent of the severity (classically ranked into types I–III). The high genetic homogeneity, coupled with the excellent results of presymptomatic treatments of patients with each of the three disease-modifying therapies available, makes SMA one of the golden candidates to genetic newborn screening (NBS) (SMA-NBS). The implementation of SMA in NBS national programmes occurring in some countries is an arising new issue that the scientific community has to address. We report here the results of the first Italian SMA-NBS project and provide some proposals for updating the current molecular diagnostic scenario.

    Methods The screening test was performed by an in-house-developed qPCR assay, amplifying SMN1 and SMN2. Molecular prognosis was assessed on fresh blood samples.

    Results We found 15 patients/90885 newborns (incidence 1:6059) having the following SMN2 genotypes: 1 (one patient), 2 (eight patients), 2+c.859G>C variant (one patient), 3 (three patients), 4 (one patient) or 6 copies (one patient). Six patients (40%) showed signs suggestive of SMA at birth. We also discuss some unusual cases we found.

    Conclusion The molecular diagnosis of SMA needs to adapt to the new era of the disease with specific guidelines and standard operating procedures. In detail, SMA diagnosis should be felt as a true medical urgency due to therapeutic implications; SMN2 copy assessment needs to be standardised; commercially available tests need to be improved for higher SMN2 copies determination; and the SMN2 splicing-modifier variants should be routinely tested in SMA-NBS.

    • Genetics, Population
    • Neonatal Screening
    • Neuromuscular Diseases
    • Genetic Testing

    Data availability statement

    Data sharing not applicable as no datasets generated and/or analysed for this study.

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    Data availability statement

    Data sharing not applicable as no datasets generated and/or analysed for this study.

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    Footnotes

    • EA and AV contributed equally.

    • Collaborators Italian SMA-NBS group: Maria Accardo, Beatrice Gambi, Rino Agostiniani, Simonetta Giampaoli, Ubah Farah Ahmed, Carlo Giannini, Concetta Alecci, Valerio Giardini, Antonella Amendolea, Monica Guarguagli, Monica Bartolucci, Cristina Haass, Ivana Belisario, Isabella Innocenti, Paola Belluomini, Maria Cristina Innocenti Berti, Claudia Bernardini, Claudia Maggi, Roberto Bernardini, Letizia Magi, Luisa Bertò, Roccuccia Malorgio, Rita Bini, Giovanna Maragliano, Leonardo Bolgia, Vita Maraglino, Mario Boscioni, Anna Marotta, Giorgio Bracaglia, Cristina Martini, Elisa Brachini, Palmina Martufi, Elisa Bruschi, Stefania Mastropasqua, Monica Campa, Maria Rosaria Matera, Monica Caprilli, Graziano Memmini, Simona Carcione, Angela Mendicino, Angelo Cardiello, Sabrina Mercurio, Francesco Cartolano, Alessandra Meucci, Alessandra Casati, Osvaldo Milita, Sandra Ceccarelli, Zeudi Morano, Marzia Chiellini, Eleonora Nardi, Rossella Ciccotti, Sandra Novelli, Elena Cioli, Luigi Padovano, Flavio Civitelli, Maria Gabriella Palermo, Maria Giovanna Colella, Serena Pascucci, Luigina Coppotelli, Caterini Patrizia, Francesco Crescenzi, Assunta Percoco, Carlo Dani, Stefania Petrolati, Roberto Danieli, Rosanna Pitaro, Tamara De Angelis, Marilena Raponi, Mauro De Martinis, Francesco Riccobene, Elena degl’Innocenti, Giovanni Rosa, Laura Del Sette, Amanda Roversi, Ambrogio Di Paolo, Sabrina Sadocco, Luigi Di Ruzza, Emanuela Santarelli, Rosalia Di Silvio, Luca Tafi, Dituri Francesco, Barbara Tomasini, Gwenna Egho, Martha Traupe, Daniela Emili, Angelina Vaccaro, Luca Filippo, Pierluigi Vasarri, Claudia Foglia, Valentina Ventura, Francesco Gabriellini, Stefano Vitale, Luigi Gagliardi, Anna Maria Zingoni, Annamaria Gallo.

    • Contributors Conceptualisation: FDT, EM, MAD and EB; data curation: SS, EA, AN and AV: formal analysis: FDT, EA and AV; funding acquisition: FDT; investigation: TG, AD'A, GV, RS, FG, AD'A, SC, AP, MP, CT, MD, MS, IB, AL, GL, MG and MP; methodology: SF, AN, SS and MVF; project administration and writing (original draft): FDT, EA and AV; software: SS; supervision: FDT and MAD; writing (review and editing): any authors; informed consent from families and neonates’ enrolment: Italian SMA-NBS group; guarantor and responsible for the entire content of the study: FDT.

    • Funding This study was supported by Biogen Italia (IIT #ITA-NBS-17-11262).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.